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OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

Abstract Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the “Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit” to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions. Graphical Abstract

We here report the purification of a novel member of the galectin family, the β-galactoside-binding lectin hRTL, from the marine sponge Chondrilla australiensis. The hRTL lectin is a tetrameric proto-type galectin with a subunit molecular weight of 15.5 kDa, consisting of 141 amino acids and sharing 92% primary sequence identity with the galectin CCL from the congeneric species C. caribensis. Transcriptome analysis allowed for the identification of additional sequences belonging to the same family, bringing the total number of hRTLs to six. Unlike most other galectins, hRTLs display a 23 amino acid-long signal peptide that, according to Erdman degradation, is post-translationally cleaved, leaving an N-terminal end devoid of acetylated modifications, unlike most other galectins. Moreover, two hRTLs display an internal insertion, which determines the presence of an unusual loop region that may have important functional implications. The characterization of the glycan-binding properties of hRTL revealed that it had high affinity towards TF-antigen, sialyl TF, and type-1 N-acetyl lactosamine with a Galβ1-3 structure. When administered to DLD-1 cells, a colorectal carcinoma cell line expressing mucin-associated TF-antigen, hRTL could induce glycan-dependent cytotoxicity.

SeviL, a galactoside-binding lectin previously isolated from the mussel Mytilisepta virgata, was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel β-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.

Background: The mechanism of allergic reactions to COVID-19 mRNA vaccines has not been clarified. Polyethylene glycol (PEG) is a potential antigen in the components of vaccines. However, there is little evidence that allergy after COVID-19 mRNA vaccination is related to PEG. Furthermore, the role of polysorbate (PS) as an antigen has also not been clarified. The objective of this study was to investigate whether PEG and PS allergies are reasonable causes of allergic symptoms after vaccination by detecting PEG-specific and PS-specific antibodies. Methods: Fourteen patients who developed immediate allergic reactions to BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines and nineteen healthy controls who did not present allergic symptoms were recruited. Serum PEG-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) and PS-specific IgE and IgG were measured by enzyme-linked immunosorbent assay. Skin tests using PEG-2000 and PS-80 were applied to five patients and three controls. Results: Serum levels of PEG-specific IgE and IgG in patients with immediate allergic reactions to the COVID-19 mRNA vaccine were higher than those in the control group. Serum levels of PS-specific IgE in patients with allergy to the vaccine were higher than those in patients of the control group. Intradermal tests using PEG verified the results for PEG-specific IgE and IgG. Conclusions: The results suggest that PEG is one of the antigens in the allergy to COVID-19 mRNA vaccines. Cross-reactivity between PEG and PS might be crucial for allergy to the vaccines. PEG-specific IgE and IgG may be useful in diagnosing allergy to COVID-19 mRNA vaccines.

Abstract Aim The rapid response system (RRS) was initially aimed to improve patient outcomes. Recently, some studies have implicated that RRS might facilitate do‐not‐attempt‐resuscitation (DNAR) orders among patients, their families, and healthcare providers. This study aimed to examine the incidence and factors independently associated with DNAR orders newly implemented after RRS activation among deteriorating patients. Methods This observational study assessed patients who required RRS activation between 2012 and 2021 in Japan. We investigated patients’ characteristics and the incidence of new DNAR orders after RRS activation. Furthermore, we used multivariable hierarchical logistic regression models to explore independent predictors of new DNAR orders. Results We identified 7904 patients (median age, 72 years; 59% male) who required RRS activation at 29 facilities. Of the 7066 patients without pre‐existing DNAR orders before RRS activation, 394 (5.6%) had new DNAR orders. Multivariable hierarchical logistic regression analyses revealed that new DNAR orders were associated with age category (adjusted odds ratio [aOR], 1.56; 95% confidence interval, 1.12–2.17 [65–74 years old reference to 20–64 years old], aOR, 2.56; 1.92–3.42 [75–89 years old], and aOR, 6.58; 4.17–10.4 [90 years old]), malignancy (aOR, 1.82; 1.42–2.32), postoperative status (aOR, 0.45; 0.30–0.71), and National Early Warning Score 2 (aOR, 1.07; 1.02–1.12 [per 1 score]). Conclusion The incidence of new DNAR orders was one in 18 patients after RRS activation. The factors associated with new DNAR orders were age, malignancy, postoperative status, and National Early Warning Score 2.

Although inadequate research support for intensivists can be one major reason of the poor research productivity, no study has investigated the current research environment in critical care medicine in Asia. The objective of this study was to describe Asian academia in critical care from the research environment perspective. We conducted a cross-sectional questionnaire survey targeting all physician members of the Societies of Intensive/Critical Care Medicine in Japan, South Korea, and Singapore. We collected the characteristics of the participants and their affiliated institutions and the research environment. The outcome was the number of peer-reviewed publications. Multivariable logistic regression analyses examined the association between the outcome and the following five research environmental factors (i.e., country of the respondents, availability of secured time for research activities or research supporting staff for the hospital, practice at a university-affiliated hospital, and years of clinical practice of 10 years or longer). Four hundred ninety responded (overall response rate: 5.6%) to the survey between June 2019 and January 2020. Fifty-five percent worked for a university-affiliated hospital, while 35% worked for a community hospital. Twenty-four percent had secured time for research within their full-time work hours. The multivariable logistic model found that a secured time for the research activities [odds ratio (OR): 2.77; 95% confidence interval (CI), 1.46–5.24], practicing at a university-affiliated hospital (OR: 2.61; 95% CI, 1.19–5.74), having clinical experience of 10 years or longer (OR:11.2; 95%CI, 1.41–88.5), and working in South Korea (OR: 2.18; 95% CI, 1.09–4.34, Reference: Japan) were significantly associated with higher research productivity. Intensivists in the three countries had limited support for their research work. Dedicated time for research was positively associated with the number of research publications.

Coronavirus disease 2019 (COVID-19) and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with cardiovascular complications. Here, we report a case of right-sided heart failure caused by constrictive pericarditis that developed after the administration of messenger ribonucleic acid (mRNA) vaccine against SARS-CoV-2. A 70-year-old woman presented with body weight gain, peripheral edema, and dyspnea on effort, which developed over a period of 1 week after the second dose of vaccine. The jugular venous pressure was high with a prominent y descent (Friedreich's sign) and paradoxical increase on inspiration (Kussmaul's sign). The results of IgM and IgG testing specific to SARS-CoV-2 spike and nucleocapsid proteins indicated the presence of mRNA vaccine-induced antibody and were not suggestive of COVID-19 infection. Echocardiography showed pericardial thickening and septal bounce of the interventricular septum. Computed tomography (CT) also showed pericardial thickening compared with the results of the previous CT scan performed 4 months earlier. A diagnosis of right-sided heart failure due to constrictive pericarditis was confirmed on the basis of pressure analysis during cardiac catheterization.

Abstract The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Abstract Since the start of the coronavirus disease 2019 (COVID-19) pandemic, it has remained unknown whether conventional risk prediction tools used in intensive care units are applicable to patients with COVID-19. Therefore, we assessed the performance of established risk prediction models using the Japanese Intensive Care database. Discrimination and calibration of the models were poor. Revised risk prediction models are needed to assess the clinical severity of COVID-19 patients and monitor healthcare quality in ICUs overwhelmed by patients with COVID-19.

Abstract Background The Acute Physiology and Chronic Health Evaluation (APACHE) III-j model is widely used to predict mortality in Japanese intensive care units (ICUs). Although the model’s discrimination is excellent, its calibration is poor. APACHE III-j overestimates the risk of death, making its evaluation of healthcare quality inaccurate. This study aimed to improve the calibration of the model and develop a Japan Risk of Death (JROD) model for benchmarking purposes. Methods A retrospective analysis was conducted using a national clinical registry of ICU patients in Japan. Adult patients admitted to an ICU between April 1, 2018, and March 31, 2019, were included. The APACHE III-j model was recalibrated with the following models: Model 1, predicting mortality with an offset variable for the linear predictor of the APACHE III-j model using a generalized linear model; model 2, predicting mortality with the linear predictor of the APACHE III-j model using a generalized linear model; and model 3, predicting mortality with the linear predictor of the APACHE III-j model using a hierarchical generalized additive model. Model performance was assessed with the area under the receiver operating characteristic curve (AUROC), the Brier score, and the modified Hosmer–Lemeshow test. To confirm model applicability to evaluating quality of care, funnel plots of the standardized mortality ratio and exponentially weighted moving average (EWMA) charts for mortality were drawn. Results In total, 33,557 patients from 44 ICUs were included in the study population. ICU mortality was 3.8%, and hospital mortality was 8.1%. The AUROC, Brier score, and modified Hosmer–Lemeshow p value of the original model and models 1, 2, and 3 were 0.915, 0.062, and < .001; 0.915, 0.047, and < .001; 0.915, 0.047, and .002; and 0.917, 0.047, and .84, respectively. Except for model 3, the funnel plots showed overdispersion. The validity of the EWMA charts for the recalibrated models was determined by visual inspection. Conclusions Model 3 showed good performance and can be adopted as the JROD model for monitoring quality of care in an ICU, although further investigation of the clinical validity of outlier detection is required. This update method may also be useful in other settings.

Abstract Background Patients with hypertrophic cardiomyopathy (HCM) in sinus rhythm commonly show the fourth heart sound (S4). The lack of S4 may be a marker of impaired atrial function in HCM patients with sinus rhythm. Methods and Results This retrospective study consisted of 47 patients with HCM who had undergone phonocardiography and a cardiopulmonary exercise test. The primary outcome was a composite of cardiac death, stroke, hospitalization for worsening heart failure, and newly developed atrial fibrillation (AF). S4 was detected in 38 of 43 patients with sinus rhythm (88%). Peak oxygen consumption was the highest in 38 sinus rhythm patients with S4 (23.6 ± 5.6 mL/kg/min), middle in five sinus rhythm patients without S4 (19.3 ± 6.7 mL/kg/min), and lowest in four patients with AF (15.7 ± 3.3 mL/kg/min, p = 0.01). After a median of 40.5 months, the incidence of the primary outcome was higher in patients without S4 than in those with S4 (33% vs. 8%; hazard ratio, 6.17; 95% confidence interval, 1.02 – 37.4; p = .04) and higher in sinus rhythm patients without S4 than in those with S4 (60% vs. 8%; hazard ratio, 12.05; 95% confidence interval, 2.31 – 71.41; p = .007). Conclusions The absence of S4 on phonocardiography was associated with impaired exercise tolerance and adverse cardiac events in HCM patients with sinus rhythm.

Technetium-99m-pyrophosphate (99mTc-PYP) has been used, in combination with thallium-201, to estimate the site and extent of myocardial infarcts. We report a case of acute myocardial infarction with severe coronary disease in which the distribution of 99mTc-PYP was extensive. A 78-year-old man presented with dyspnea, and a diagnosis of non-ST-segment elevation acute myocardial infarction was made. Emergency coronary angiography revealed total occlusion of the proximal portion of the right coronary artery and left circumflex coronary artery with collateral flow from the left anterior descending coronary artery, which also had severe stenoses. Given his comorbidities and preferences, subsequent angioplasty was waived. Dual myocardial scintigraphic imaging, which was performed four days after admission, demonstrated slightly reduced thallium-201 uptake in the inferior wall and apex, whereas 99mTc-PYP was positive in the entire left ventricular subendocardial region and the free wall of the right ventricle. His clinical course was uneventful with conservative treatment and the patient was discharged 20 days after admission in a stable condition.

Background Coronavirus disease (COVID‐19), an infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J‐SSCG) 2020 Special Committee created the Japanese Rapid/Living recommendations on drug management for COVID‐19 using the experience of creating the J‐SSCG. Methods The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of recommendations. The first edition of this guideline was released on September 9, 2020, and this is the revised edition (version 5.0; released on July 15, 2022). Clinical questions (CQs) were set for the following 10 drugs: favipiravir (CQ1), remdesivir (CQ2), corticosteroids (CQ4), tocilizumab (CQ5), anticoagulants (CQ7), baricitinib (CQ8), casirivimab/imdevimab (CQ9‐1), sotrovimab (CQ9‐2), molnupiravir (CQ10), and nirmatrelvir/ritonavir (CQ11). Recommendations Favipiravir is not suggested for all patients with COVID‐19 (GRADE 2C). Remdesivir is suggested for patients with mild COVID‐19 who do not require oxygen, and patients with moderate COVID‐19 requiring supplemental oxygen/hospitalization (both GRADE 2B). Corticosteroids are recommended for moderate and severe COVID‐19 (GRADE 1B, 1A). However, their administration is not recommended for mild COVID‐19 (GRADE 1B). Tocilizumab is suggested for moderate and severe COVID‐19 (GRADE 2B, 2C). Anticoagulant administration is recommended for moderate and severe COVID‐19 (Good Practice Statement). Baricitinib is suggested for moderate and severe COVID‐19 (both GRADE 2C). Casirivimab/imdevimab and sotrovimab are recommended for mild COVID‐19 (both GRADE 2C). Molnupiravir and nirmatrelvir/ritonavir are recommended for mild COVID‐19 (both GRADE 2C). SARS‐CoV‐2 mutant strains emerge occasionally, and each time, the treatment policy at clinics is forced to change drastically. We ask health‐care professionals in the field to refer to the recommendations in these guidelines and use these to keep up to date with COVID‐19 epidemiological information.

Selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and noradrenergic and specific serotonergic antidepressants (NaSSAs) are broadly used for the treatment of depression. Depression is one of the most common psychiatric disorders in pregnant women and SSRIs are commonly prescribed for depression during pregnancy. The placenta regulates the transport of nutrients and oxygen between the maternal and fetal circulation, and is essential for the survival and growth of the fetus. The present study investigated the effects of antidepressants on human placental BeWo cells.BeWo cell viability was significantly decreased following exposure to sertraline (SSRI), paroxetine (SSRI), fluvoxamine (SSRI), and duloxetine (SNRI), whereas escitalopram (SSRI), venlafaxine (SNRI), and mirtazapine (NaSSA) showed little or no effects. Extracellular lactate dehydrogenase activity was increased by sertraline, paroxetine, fluvoxamine, and duloxetine, indicating toxicity to the cells. Sertraline increased the production of cellular reactive oxygen species (ROS) and decreased the mitochondrial membrane potential. Sertraline decreased the cellular ATP content in a time and concentration-dependent manner. Caspase-3/7 activity and apoptotic cells, detected using the phosphatidylserine-specific fluorescent probe Apotracker Green, were increased by sertraline.Our findings suggest that antidepressants, such as sertraline, paroxetine, fluvoxamine, and duloxetine, induce toxicity in human placental BeWo cells. Sertraline may induce ROS-dependent apoptosis in human placental cells. These results are useful for further studies to determine the optimal dosage of antidepressants for pregnant women.

Expanding elderly populations are a major social challenge in advanced countries worldwide and have led to a rapid increase in the number of elderly patients in intensive care units (ICUs). Innovative advances in medical technology have enabled lifesaving of patients in ICUs, but there remain various problems to improve their long‐term prognoses. Post‐intensive care syndrome (PICS) refers to physical, cognition, and mental impairments that occur during ICU stay, after ICU discharge or hospital discharge, as well as the long‐term prognosis of ICU patients. Its concept also applies to pediatric patients (PICS‐p) and the mental status of their family (PICS‐F). Intensive care unit‐acquired weakness, a syndrome characterized by acute symmetrical limb muscle weakness after ICU admission, belongs to physical impairments in three domains of PICS. Prevention of PICS requires performance of the ABCDEFGH bundle, which incorporates the prevention of delirium, early rehabilitation, family intervention, and follow‐up from the time of ICU admission to the time of discharge. Diary, nutrition, nursing care, and environmental management for healing are also important in the prevention of PICS. This review outlines the pathophysiology, prevention, and future directions of PICS.

Isolated septal myocardial infarction is an uncommon condition with diagnostic difficulty due to small infarction size and anatomical variations. We report a case of isolated septal myocardial infarction, in which the diagnosis was confirmed not by electrocardiographic, echocardiographic, or angiographic findings, but by nuclear imaging. A 46-year-old man with chest discomfort exhibited ST-segment elevations in leads V1 and V2, and borderline abnormalities of the septal wall motion on echocardiography. Emergency coronary angiography demonstrated delayed flow in the second septal branch of the left anterior descending coronary artery. Intravascular ultrasound showed plaque in the proximal portion of the septal branch without evidence of plaque rupture. No balloon angioplasty or stent implantation was required because the flow delay in the septal branch disappeared after the intravascular ultrasound procedure. Myocardial perfusion-metabolism mismatch, as assessed by resting thallium-201 and iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid, was seen in the mid-septal region.

The coronavirus disease (COVID‐19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J‐SSCG) 2020 Special Committee created the Japanese rapid/living recommendations on drug management for COVID‐19 using the experience of creating the J‐SSCGs. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on 9 September, 2020, and this document is the revised edition (version 3.1) (released 30 March, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ2), hydroxychloroquine (CQ3), corticosteroids (CQ4), tocilizumab (CQ5), ciclesonide (CQ6), and anticoagulants (CQ7). Favipiravir is recommended for patients with mild COVID‐19 not requiring supplemental oxygen (GRADE 2C); remdesivir for moderate COVID‐19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Hydroxychloroquine is not recommended for all COVID‐19 patients (GRADE 1B). Corticosteroids are recommended for moderate COVID‐19 patients requiring supplemental oxygen/hospitalization (GRADE 1B) and severe COVID‐19 patients requiring ventilator management/intensive care (GRADE 1A); however, their use is not recommended for mild COVID‐19 patients not requiring supplemental oxygen (GRADE 1B). Tocilizumab is recommended for moderate COVID‐19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Anticoagulant therapy is recommended for moderate COVID‐19 patients requiring supplemental oxygen/hospitalization and severe COVID‐19 patients requiring ventilator management/intensive care (GRADE 2C). We hope that these clinical practice guidelines will aid medical professionals involved in the care of COVID‐19 patients.

This study examined the effects of microtubule-targeting anticancer drugs (paclitaxel, cabazitaxel, and eribulin) on the expression of drug efflux transporter P-glycoprotein, which is encoded by MDR1. Paclitaxel and eribulin induced MDR1 promoter activity in a concentration-dependent manner, while cabazitaxel had little effect in human intestinal epithelial LS174T cells. Overexpression of the nuclear receptor pregnane X receptor (PXR) gene (NR1I2) enhanced paclitaxel- and eribulin-induced MDR1 activation, but expression of the nuclear receptor co-repressor silencing mediator for retinoid and thyroid receptors (SMRT) gene (NCOR2) repressed MDR1 activation. Eribulin increased the mRNA and protein expression of P-glycoprotein in LS174T cells. Cellular uptake of rhodamine 123 and calcein-acetoxymethyl ester (calcein-AM), P-glycoprotein substrates, decreased in paclitaxel- or eribulin-treated LS174T cells. Eribulin also increased MDR1 promoter activity in human breast cancer MCF7 cells. The results suggest that the microtubule-targeting anticancer drug eribulin can induce the drug efflux transporter P-glycoprotein via PXR in human intestinal and breast cancer cells and thus influence the efficacy of anticancer drugs. Keywords: P-glycoprotein, Drug transporter, Induction, Eribulin mesylate, Drug–drug interaction

Abstract Background and purpose The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] https://doi.org/10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc. This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine. Methods Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members. Results A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs. Conclusions Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

Abstract Background Sepsis is one of the leading causes of mortality among children worldwide. Unfortunately, however, reliable evidence was insufficient in pediatric sepsis and many aspects in clinical practice actually depend on expert consensus and some evidence in adult sepsis. More recent findings have given us deep insights into pediatric sepsis since the publication of the Surviving Sepsis Campaign guidelines 2012. Main text New knowledge was added regarding the hemodynamic management and the timely use of antimicrobials. Quality improvement initiatives of pediatric “sepsis bundles” were reported to be successful in clinical outcomes by several centers. Moreover, a recently published global epidemiologic study (the SPROUT study) did not only reveal the demographics, therapeutic interventions, and prognostic outcomes but also elucidated the inappropriateness of the current definition of pediatric sepsis. Conclusions With these updated knowledge, the management of pediatric sepsis would be expected to make further progress. In addition, it is meaningful that the fundamental data on which future research should be based were established through the SPROUT study.

Human parechovirus type 3 (HPeV3) can cause serious conditions in neonates, such as sepsis and encephalitis, but data for adults are lacking. The case of a pregnant woman with HPeV3 infection is reported herein. A 28-year-old woman at 36 weeks of pregnancy was admitted because of myalgia and muscle weakness. Her grip strength was 6.0 kg for her right hand and 2.5 kg for her left hand. The patient’s symptoms, probably due to fasciitis and not myositis, improved gradually with conservative treatment, however labor pains with genital bleeding developed unexpectedly 3 days after admission. An obstetric consultation was obtained and a cesarean section was performed, with no complications. A real-time PCR assay for the detection of viral genomic ribonucleic acid against HPeV showed positive results for pharyngeal swabs, feces, and blood, and negative results for the placenta, umbilical cord, umbilical cord blood, amniotic fluid, and breast milk. The HPeV3 was genotyped by sequencing of the VP1 region. The woman made a full recovery and was discharged with her infant in a stable condition.

Although thallium-201 exercise scintigraphy has been established for the detection of myocardial ischemia and viability, little is known regarding the myocardial thallium-201 kinetics during angioplasty. Herein, we report a 77-year old man with angina pectoris, in whom serial myocardial imaging after a single dose of thallium-201 was helpful in identifying not only the culprit lesion and myocardial viability, but also the dynamic changes in myocardial perfusion during angioplasty. Thallium-201 images after exercise showed a perfusion defect in the inferior wall, with a trivial redistribution 3 hours after the exercise and a marked improvement 24 hours later. Coronary angiography, performed 27 hours after exercise scintigraphy, showed severe stenosis in the right coronary artery. Guidewire crossing of the lesion interrupted the antegrade flow, which was restored after balloon dilation and stent implantation. Thallium-201 images, 2 hours after angioplasty (i.e., 30 hours after exercise), showed a decreased tracer uptake in the inferior wall, which improved the next day (i.e., 48 hours after exercise). Cardiac biomarkers were negative in the clinical course.